Cannabis sativa L., also known as marijuana, has been used for centuries for its psychoactive and medicinal properties [82]. The term cannabinoid was originally coined for any compound isolated from Cannabis [85]. However, today it refers to any compound that demonstrates similar pharmacology to that of Δ9-THC [83]. Δ9-THC and related cannabinoids exert their activity on the cannabinoid receptors (CBRs), which were discovered and characterized in the early 1990s [86,87]. There are two main CBR subtypes, CB1 (CB1R) and CB2 (CB2R), both of which are members of the class A GPCR receptor subfamily [88]. CB1Rs are located throughout the body, with the highest percentage being in the central nervous system (CNS), and are involved in many physiological processes [83]. CB2Rs on the other hand are mainly prevalent in the periphery and are interrelated with the immune system [88,89]. Both of the cannabinoid receptors couple through inhibitory G proteins (Gi/o), which leads to the inhibition of adenylyl cyclase and certain voltage-sensitive calcium channels and activates inward-rectifying potassium channels [88,90]. The cannabinoids represent a structurally different family, in which there are four distinct classes: classical cannabinoids, which includes Δ9-THC and other pyran-containing analogues; non-classical cannabinoids, which lack the pyran ring such as CP-55,940; aminoalkylindoles exemplified by WIN-55,212-2; and the eicosanoids, which include the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their derivatives (FIG. 1) [83].
In 1992, a group of scientist at Sterling-Winthrop synthesized pravadoline (FIG. 1), an aminoalkylindole, for the purpose of developing a non-steroidal anti-inflammatory drug (NSAD) [91]. In addition to exhibiting prostaglandin inhibition, it was also shown that it inhibits contractions of the electrically stimulated mouse vas deferens [92,93]. Pravadoline and related derivatives were later shown to interact with cannabinoid CB1Rs and exhibit classical cannabinoid pharmacology in vivo [91,94]. Their interesting pharmacology prompted many researchers into the development of preliminary structure-activity relationships (SAR) for their interaction with the cannabinoid receptors. Reports of aminoalkylindole SAR came in promptly and in the mid-late 1990s Huffman et al. described a series of aminoalkyindoles that possess excellent in vitro and in vivo activity at the same receptor as Δ9-THC [95-97]. Among the most interesting in the Huffman series were JWH-018, JWH-073, and JWH-200 (FIG. 2A), which exhibited differential selectivity towards CB1Rs and CB2Rs and were shown to be more potent than Δ9-THC [96,97]. Because of their high activity at the CBRs, these compounds became the main components of an incense blend known as K2/Spice. Despite their increasing popularity, very little is known regarding K2/Spice metabolism, pharmacology, and toxicity.
It has been shown that chronic ethanol (EtOH) exposure down-regulates CB1Rs and increases the brain concentration of AEA and 2-AG [98,99]. In addition, Wang et al., demonstrated that CB1R antagonist rimonabant (SR141716A, FIG. 3) reduces EtOH intake in C57B1/6J mice to levels comparable with that of CB1+/+ mice [101]. Furthermore, Hungund et al., also demonstrated that CB1R knock-out mice exhibit reduced voluntary alcohol consumption as compared to wild type mice [102]. Despite all the research being done with rimonabant, this CB1R antagonist was withdrawn from the market in 2007 because of its severe side-effects, which include headaches, nausea, depression, anxiety and suicidal ideation [88,103].
This further supports the notion that novel CB1R antagonist are needed as probes for further investigation of the cannabinoid system, a therapeutic target of interest to numerous research programs around the country. In addition to the studies done on the involvement of the CB1Rs in substance abuse, it was recently shown that CB2Rs may be implicated in substance abuse as well. Specifically, Xi et al., reported that systematic administration of the CB2R agonist JWH-133 (FIG. 3), dose-dependently inhibited intravenous cocaine self-administration in wild-type and CB1R-deficient mice, but not in CB2R-deficient mice [104,105]. This observation was prevented with the pre-treatment of the CB2R antagonist AM630 (FIG. 3), which suggests that the seen effects are mediated by CB2Rs [104]. To investigate if these observations were in fact mediated by brain CB2Rs and not peripheral CB2Rs, the authors intranasally microinjected JWH-133 and saw a dose-dependent inhibition of cocaine self-administration, which was not seen with an intravenous injection of same quantities of the agonist [104]. This in turn confirmed that these observations were indeed mediated by brain CB2Rs.
Activation of cannabinoid 1 receptors (CB1Rs) results in increased hunger and food intake [1].
The health impacts of obesity on the modern Western world are well-known and documented. Obesity is a chronic condition that is associated with the comorbidities of type II diabetes, dyslipidemia, hypertension, cardiovascular disease, and non-alcoholic steatohepatitis (NASH), most of which have inflammatory components. The results of obesity for the individual are often a decrease in longevity and quality of life. In 2008, the estimated financial burden obesity placed on healthcare costs in the United States was a staggering $147 billion, which will presumably continue to increase.
Alcohol and drug addiction and abuse are also major problems in society. New and better agents and methods for treating alcohol and drug abuse and promoting recovery are needed.